Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/425—Thiazoles
  • A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
  • A61P11/06—Antiasthmatics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
  • A61P11/16—Central respiratory analeptics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P13/00—Drugs for disorders of the urinary system
  • A61P13/12—Drugs for disorders of the urinary system of the kidneys
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
  • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
  • A61P17/04—Antipruritics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
  • A61P17/06—Antipsoriatics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
  • A61P17/14—Drugs for dermatological disorders for baldness or alopecia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P19/00—Drugs for skeletal disorders
  • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
  • A61P21/02—Muscle relaxants, e.g. for tetanus or cramps
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P27/00—Drugs for disorders of the senses
  • A61P27/02—Ophthalmic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
  • A61P35/02—Antineoplastic agents specific for leukemia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/02—Immunomodulators
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/02—Immunomodulators
  • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/08—Antiallergic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P5/00—Drugs for disorders of the endocrine system
  • A61P5/14—Drugs for disorders of the endocrine system of the thyroid hormones, e.g. T3, T4
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
  • A61P7/06—Antianaemics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
  • C07C237/28—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton
  • C07C237/40—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having the nitrogen atom of the carboxamide group bound to a carbon atom of a six-membered aromatic ring
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
  • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
  • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
  • C07D213/81—Amides; Imides
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
  • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
  • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
  • C07D213/81—Amides; Imides
  • C07D213/82—Amides; Imides in position 3
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
  • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
  • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
  • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D231/38—Nitrogen atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
  • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
  • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D233/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
  • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
  • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
  • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
  • C07D239/32—One oxygen, sulfur or nitrogen atom
  • C07D239/42—One nitrogen atom
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
  • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
  • C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
  • C07D263/34—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D263/48—Nitrogen atoms not forming part of a nitro radical
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
  • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
  • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
  • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D277/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
  • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
  • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
  • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
  • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
  • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

• the present invention relates to cyclic compounds and salts thereof, to methods of using such compounds in treating protein tyrosine kinase- associated disorders such as immunologic and oncologic disorders, and to pharmaceutical compositions containing such compounds.
• PTKs Protein tyrosine kinases
• PTKs comprise, inter alia, receptor tyrosine kinases (RPTKs), including members of the epidermal growth factor kinase family (e.g., HER1 and HER2), platelet derived growth factor (PDGF), and kinases that play a role in angiogenesis (Tie-2 and KDR); and, in addition, non-receptor tyrosine kinases, including members of the Syk, JAK and Src (e.g.
• PTK inhibitors can thus impact a wide variety of oncologic and immunologic disorders. Such disorders may be ameliorated by selective inhibition of a certain receptor or non-receptor PTK, such as Lck, or due to the homology among PTK classes, by inhibition of more than one PTK by an inhibitor.
• Lck a PTK of particular interest is Lck which is found in T cells where it is involved in phosphorylating key protein substrates. It is required for productive antigen receptor signaling and cell activation.
• T cell receptor (TCR) zeta chain In the absence of Lck activity, the T cell receptor (TCR) zeta chain is not phosphorylated, the kinase ZAP-70 is not activated, and Ca 2+ mobilization essential for T cell activation does not occur (see Weiss, A.
• Inhibitors of Lck are thus useful in the treatment of T-cell mediated disorders such as chronic diseases with an important T cell component, for example rheumatoid arthritis, multiple sclerosis and lupus, as well as acute diseases where T cells are known to play an essential role, for example acute transplant rejection and delayed-type hypersensitivity (DTH) reactions.
• T-cell mediated disorders such as chronic diseases with an important T cell component, for example rheumatoid arthritis, multiple sclerosis and lupus, as well as acute diseases where T cells are known to play an essential role, for example acute transplant rejection and delayed-type hypersensitivity (DTH) reactions.
• DTH delayed-type hypersensitivity
• the present invention provides cyclic compounds of the following formula I and salts thereof, for use as protein tyrosine kinase inhibitors:
• R 6 is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, aralkyl, heterocyclo, or heterocycloalkyl, each of which is unsubstituted or substituted with Z v Z 2 and one or more (preferably, one or two) groups Z 3 ;
• R 2 and R 3 are each independently: (1) hydrogen or R 6 ;
• (1) ' are each independently hydrogen or R 6 ; (2) -Z 4 -N(R 9 )-Z 6 -NR 10 R U ;
• R 7 and R 8 may together be alkylene, alkenylene or heteroalkyl, completing a 3- to 8-membered saturated or unsaturated ring with the nitrogen atom to which they are attached, which ring is unsubstituted or substituted with Z v Z 2 and Z 3 ; or
• any two of R 9 , R 10 and R u may together be alkylene or alkenylene completing a 3- to 8-membered saturated or unsaturated ring together with the nitrogen atoms to which they are attached, which ring is unsubstituted or substituted with Z v Z 2 and Z 3 ;
• R 13 is:
• R 14 is:
• R 15 is: (1) hydrogen
• cycloalkyl and Z 3 are each independently:
• Z 6 is (i) alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, aralkyl, alkylaryl, cycloalkylaryl, heterocyclo, or heterocycloalkyl; (ii) a group (i) which is itself substituted by one or more of the same or different groups (i); or (iii) a group (i) or (ii) which is substituted by one or more of the following groups (2) to (16) of the definition of Z x , Z 2 and Z 3 ; (2) -OH or -OZ 6 ;
• any two of Z v Z 2 , and Z 3 may together be alkylene or alkenylene completing a 3- to 8-membered saturated or unsaturated ring together with the atoms to which they are attached; or (16) any two of Z x , Z 2 , and Z 3 may together be -0-(CH 2 ) r -0- ,where r is 1 to 5, completing a 4- to 8-membered saturated or unsaturated ring together with the atoms to which they are attached; Z 4 and Z 5 are each independently:
• (1) are each independently hydrogen or Z 6 ;
• Z 7 and Z 8 , or Z 6 and Z 10 may together be alkylene or alkenylene, completing a 3- to 8-membered saturated or unsaturated ring together with the atoms to which they are attached, which ring is unsubstituted or substituted with Z v Z 2 and Z 3 ; or
• Z 7 or Z 8 together with Z 9 , may be alkylene or alkenylene completing a 3- to 8-membered saturated or unsaturated ring together with the nitrogen atoms to which they are attached, which ring is unsubstituted or substituted with Z v Z 2 and Z -" 3 3>
• Z u and Z 12 are each independently: (1) a single bond; (2) alkylene; (3) alkenylene; or
• n 1 or 2
• A is selected from carbon and nitrogen
• B is selected from nitrogen, oxygen and sulfur
• X g is oxygen or sulfur; and R R 2 , R 3 , R 4 and R 5 are as described above. Detailed Description of the Invention
• alk or alkyl refer to straight or branched chain hydrocarbon groups having 1 to 12 carbon atoms, preferably 1 to 8 carbon atoms.
• lower alkyl refers to alkyl groups of 1 to 4 carbon atoms.
• alkenyl refers to straight or branched chain hydrocarbon groups of 2 to 10, preferably 2 to 4, carbon atoms having at least one double bond. Where an alkenyl group is bonded to a nitrogen atom, it is preferred that such group not be bonded directly through a carbon bearing a double bond.
• alkynyl refers to straight or branched chain hydrocarbon groups of 2 to 10, preferably 2 to 4, carbon atoms having at least one triple bond.
• alkynyl group is bonded to a nitrogen / atom, it is preferred that such group not be bonded directly through a carbon bearing a triple bond.
• alkylene refers to a straight chain bridge of 1 to 5 carbon atoms connected by single bonds (e.g., -(CH2) ⁇ - wherein x is 1 to 5), which may be substituted with 1 to 3 lower alkyl groups.
• alkenylene refers to a straight chain bridge of 2 to 5 carbon atoms having one or two double bonds that is connected by single bonds and may be substituted with 1 to 3 lower alkyl groups.
• alkynylene refers to a straight chain bridge of 2 to 5 carbon atoms that has a triple bond therein, is connected by single bonds, and may be substituted with 1 to 3 lower alkyl groups.
• exemplary alkynylene groups are -C ⁇ C-, -GE -C ⁇ C-, -CH(CH3)-C ⁇ C- and _C ⁇ C-CH(C2H5)CH2-.
• aromatic cyclic groups for example 6 membered monocyclic, 10 membered bicyclic or 14 membered tricyclic ring systems
• exemplary aryl groups include phenyl, naphthyl, biphenyl and anthracene.
• cycloalkyl and “cycloalkenyl” refer to cyclic hydrocarbon groups of 3 to 12 carbon atoms.
• halogen and halo refer to fluorine, chlorine, bromine and iodine.
• unsaturated ring includes partially unsaturated and aromatic rings.
• heterocycle refers to fully saturated or unsaturated, including non-aromatic (i.e. “heterocycloalkyl) and aromatic (i.e. "heteroaryl”) cyclic groups, for example, 4 to 7 membered monocyclic, 7 to 11 membered bicyclic, or 10 to 15 membered tricyclic ring systems, which have at least one heteroatom in at least one carbon atom-containing ring.
• Each ring of the heterocychc group containing a heteroatom may have 1, 2, 3 or 4 heteroatoms selected from nitrogen atoms, oxygen atoms and/or sulfur atoms, where the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatoms may optionally be quaternized.
• the heterocychc group may be attached at any heteroatom or carbon atom of the ring or ring system.
• Exemplary monocyclic heterocychc groups include pyrrolidinyl, pyrrolyl, pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl, imidazolinyl, imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolyl, thiadiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, furyl, tetrahydrofuryl, thienyl, oxadiazolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, 4-piperidonyl, pyridinyl, pyrazinyl, pyrimidinyl, pyri
• Exemplary bicyclic heterocychc groups include indolyl, benzothiazolyl, benzoxazolyl, benzodioxolyl, benzothienyl, quinuclidinyl, quinolinyl, tetra-hydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuryl, chromonyl, coumarinyl, benzopyranyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl, furopyridinyl (such as furo[2,3-c]pyridinyl, furo[3,2-b]pyridinyl] or furo[2,3-b]pyridinyl), dihydroisoindolyl, dihydroquinazolinyl (such as 3,4-dihydro-4-oxo-quinazolin
• Exemplary tricyclic heterocychc groups include carbazolyl, benzidolyl, phenanthrolinyl, acridinyl, phenanthridinyl, xanthenyl and the like.
• heteroaryl refers to aromatic heterocychc groups.
• heteroaryl groups include pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, furyl, thienyl, oxadiazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazolyl, triazinyl, and the like.
• salts may in some cases form salts which are also within the scope of this invention.
• Reference to a compound of the formula I herein is understood to include reference to salts thereof, unless otherwise indicated.
• Salts of the compounds of the formula I may be formed, for example, by reacting a compound I with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization.
• Exemplary acid addition salts include acetates (such as those formed with acetic acid or trihaloacetic acid, for example, trifluoroacetic acid), adipates, alginates, ascorbates, aspartates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, cyclopentanepropionates, digluconates, dodecylsulfates, ethanesulfonates, fumarates, glucoheptanoates, glycerophosphates, hemisulfates, heptanoates, hexanoates, hydrochlorides, hydrobromides, hydroiodides, 2-hydroxyethanesulfonates, lactates, maleates, methanesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, oxal
• 3-phenylpropionates phosphates, picrates, pivalates, propionates, salicylates, succinates, sulfates (such as those formed with sulfuric acid), sulfonates (such as those mentioned herein), tartrates, thiocyanates, toluenesulfonates, undecanoates, and the like.
• Exemplary basic salts include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases (for example, organic amines) such as benzathines, dicyclohexylamines, hydrabamines, N-methyl-D-glucamines, N-methyl-D-glucamides, t-butyl amines, and salts with amino acids such as arginine, lysine and the like.
• the basic nitrogen-containing groups may be quaternized with agents such as lower alkyl halides (e.g.
• dialkyl sulfates e.g. dimethyl, diethyl, dibutyl, and diamyl sulfates
• long chain halides e.g. decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides
• aralkyl halides e.g. benzyl and phenethyl bromides
• Prodrugs and solvates of the compounds of the invention are also contemplated herein.
• the term "prodrug”, as employed herein, denotes a compound which, upon administration to a subject, undergoes chemical conversion by metabolic or chemical processes to yield a compound of the formula I, or a salt and/or solvate thereof.
• Solvates of the compounds of formula I are preferably hydrates. All stereoisomers of the present compounds, such as those which may exist due to asymmetric carbons on the R substituents of the compound of the formula I, including enantiomeric and diastereomeric forms, are contemplated within the scope of this invention.
• Individual stereoisomers of the compounds of the invention may, for example, be substantially free of other isomers, or may be admixed, for example, as racemates or with all other, or other selected, stereoisomers.
• the chiral centers of the present invention can have the S or R configuration as defined by the IUPAC 1974 Recommendations.
• Preferred Compounds Preferred compounds of the present invention are compounds of the formula I, and salts thereof, wherein Q is thiazole and wherein one or more, and especially all, of Z, X Xg 1? R 2 , R 3 , R 4 , and R 5 are selected from the following definitions: Z is a single bond;
• R x is selected from hydrogen, halo, alkyl, aryl, alkoxy, alkoxycarbonyl, or aryloxycarbonyl and is more preferably hydrogen;
• R 2 is hydrogen;
• R 3 is selected from -Z 4 -R 6 or -Z 13 -NR 7 R 8 and is more preferably -Z 4 -R 6 wherein Z 4 is a single bond and R 6 is aryl or heteroaryl which is unsubstituted or substituted with Z Z 2 and one or more (preferably, one or two) groups Z 3 ;
• R 4 is hydrogen
• R 5 is selected from aryl groups or heteroaryl groups which are substituted with Z v Z 2 and one or more (such as one or two) groups Z 3 .
• the compounds of the formula I may be prepared by methods such as those illustrated in the following Schemes A through E and I through XI. Solvents, temperatures, pressures, and other reaction conditions may readily be selected by one of ordinary skill in the art. All documents cited are incorporated herein by reference in their entirety. Starting materials are commercially available or readily prepared by one of ordinary skill in the art. Constituents of compounds are as defined elsewhere in the specification or as specifically defined in a scheme. The methods described herein may be carried out with starting materials and/or reagents in solution or alternatively, where appropriate, with one or more starting materials or reagents bound to a solid support (see (1) Thompson, L. A., Ellman, J.
• compound la where R 2 and R 3 are hydrogen may be formed by saponification of i , (R* is a carboxyl protecting group such as alkyl or arylalkyl) followed by reaction with amine iii by methods known in the art. Alternatively.! may be reacted with R 2 L, where L is a leaving group such as halogen (for example, in equimolar portions), optionally followed by reaction with R 3 L (for example, in equimolar portions) to form ii.
• R 2 L where L is a leaving group such as halogen (for example, in equimolar portions), optionally followed by reaction with R 3 L (for example, in equimolar portions) to form ii.
• i may be subjected to reductive amination using the appropriate aldehyde or ketone to form ii.
• the compound ii may then be saponified and reacted with amine iii, under conditions known to those skilled in the art, to form la where R 2 and/or R 3 are other than hydrogen.
• a 2-halo-compound yi can be prepared by reacting an appropriately substituted 2-amino-compound ia with copper (ii) halide and an alkyl nitrite such as tert-butyl nitrite in an aprotic solvent such as acetonitrile to form 2-halo-compound iy (see J. Het. Chem. 22, 1621 (1985)).
• Compound iv can be reduced with a reducing agent such as sodium borohydride in ethanol or aqueous tetrahydrofuran to form an alcohol, which can be oxidized with an oxidizing agent such as pyridinium chlorochromate or pyridinium dichromate to form aldehyde v.
• Compound v can be reacted with an alkyl(triphenylphosphorylidene) acetate to form carboxylate vi.
• Compound vi can be saponified and then reacted with an amine iii by methods known to those skilled in the art to form vii.
• compounds of formula lb where R 2 and R 3 are H can be formed by reacting compound vii with an appropriately substituted benzyl amine such as 4- methoxybenzyl amine to form compound ix, which can be hydrogenolyzed or treated with an acid such as trifluoromethanesulfonic acid and trifluoroacetic acid in the presence of anisole to form lb where R 2 and R 3 are hydrogen.
• a 2-amino-compound ia can be reacted with a chloroformate or dicarbonate to form x, which can be saponified and treated with an organolithium reagent to form compound xi.
• Compound xi may be reacted with an alkyl(triphenylphosphorylidene)acetate, followed by deprotection of the carbamate protecting group to form xii.
• compound Ic where R 2 and R 3 are hydrogen may be formed by saponification of xii followed by reaction with an amine R 4 R 5 NH by methods known to those skilled in the art.
• compound xii may be reacted with R 2 L where L is a leaving group such as halogen (for example, in equimolar portions), optionally followed by reaction with R 3 L (for example, in equimolar portions) to form xiii, which may be saponified and reacted with an amine R 4 R 5 NH by methods known to those skilled in the art to form Ia where R 2 and/or R 3 are other than hydrogen.
• the compounds of the formula Ia obtained in Scheme A may be converted into the corresponding thioamide Id using a reagent such as Lawesson's reagent (2,4-bis(4-methoxyphenyl)-l,3-dithia-2,4-diphosphetane-2,4- disulfide (see Bull. Soc. Chim. Belg., 87, 223 (1978)).
• Scheme E illustrates a general method for forming compound le, which is a compound of the formula I where X x and X g are each hydrogen.
• the compound of the formula Id obtained in Scheme D may be converted into the corresponding amine le by reduction, for example, by reaction with Raney nickel.
• Methods for preparing preferred substituents on the compounds I are illustrated in the following Schemes I to XI.
• Compound 1 can be treated with a base such as sodium hydride, sodium/potassium hexamethyldisilazide, or lithium diisopropylamide (LDA), and an alkylating agent R g X where X is halogen and R 2 is preferably alkyl, arylalkyl, or cycloalkylalkyl, and then saponified with an aqueous base such as potassium hydroxide to give 2.
• a base such as sodium hydride, sodium/potassium hexamethyldisilazide, or lithium diisopropylamide (LDA)
• LDA lithium diisopropylamide
• Acid 2 may be reacted with an amine iii using reaction conditions well known in the art for peptide bond synthesis (see, for example, Bodanszky and Bodanszky, The Practice of Peptide Chemistry, Springer- Verlag, 1984; Bodanszky, Principles of Peptide Synthesis,
• reagents which activate the carboxyl group of 2 for reaction with the amine iv include bis-(2-oxo-3-oxazolidinyl)phosphinic chloride (BOP chloride), benzotriazol-l-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (BOP reagent), [0-(7-azabenzotriazol-l-yl)-l, 1,3,3- tetramethyluronium] hexafluorophosphate (HATU), and carbodiimides such as dicyclohexylcarbodiimide (DCC) or 3-ethyl-3'- (dimethylamino)propylcarbodiimide (EDCI) either alone or in combination with a hydroxybenzotriazole.
• BOP chloride bis-(2-oxo-3-oxazolidinyl)phosphinic chloride
• BOP reagent benzotriazol-l-yl
• the activated ester intermediate can be isolated and then treated with the appropriate amine iv in a nonprotic solvent such as tetrahydrofuran (THF) or dimethylformamide (DMF) in the presence of a base, for example, an organic base such as sodium/potassium hexamethyldisilazide, triethylamine, diisopropylethylamine or l,8-diazabicyclo[5.4.0]undec-7- ene (DBU), or an inorganic base such as sodium, potassium or cesium carbonate or sodium or potassium hydride.
• a base for example, an organic base such as sodium/potassium hexamethyldisilazide, triethylamine, diisopropylethylamine or l,8-diazabicyclo[5.4.0]undec-7- ene (DBU), or an inorganic base such as sodium, potassium or cesium carbonate or sodium or potassium hydride.
• acid 4 where R 2 and R 3 are not hydrogen and are selected such that the nitrogen to which they are attached is non- basic, is reduced to the aldehyde 5 by methods well know in the art (see March, Advanced Organic Chemistry, Wiley, 1985).
• the acid 4_ may be converted to its corresponding ester followed by reduction with diisobutylaluminum hydride.
• the acid 4_ may be reduced to the corresponding primary alcohol, for example, by treatment with borane/THF, LiAlH 4 , or via reduction of a mixed anhydride, followed by subsequent oxidation to the aldehyde 5_using Cr(VI) (e.g., pyridinium chlorochromate, "PCC”) or under Swern or Moffatt conditions (e.g., (COCi dimethylsulfoxide).
• Cr(VI) e.g., pyridinium chlorochromate, "PCC”
• Swern or Moffatt conditions e.g., (COCi dimethylsulfoxide.
• the starting acid 4 may be obtained, for example, by saponification of ii.
• R 2 any group as defined
• R 3 acyl or thioacyl
• Scheme IV illustrates methods which may be used for the preparation of compounds Ij, Ik, II, Im and In.
• Ij, Ik, II, Im and In are compounds of the formula I where R 2 is any group as defined, R 3 is an acyl or thioacyl group, X x and Xg are not hydrogen, and R t is not a primary or secondary amine.
• Ij, Ik, II, Im and In have other particular substituents which are specified in this Scheme and below.
• the starting compound Ii can be prepared by suitable methods described in Schemes A and D.
• Amide Ij can be prepared by treatment of amine compound Ii with a carboxylic acid 7 in the presence of reagents which activate the carboxyl group for reaction as described above, for example BOP reagent, HATU, and carbodiimides such as DCC or EDCI either alone or in combination with a hydroxybenztriazole.
• the acid halide 8 may be reacted with amine compound Ii in the presence of an acid scavenger such as diisopropylethylamine.
• the corresponding thioamide Ik can be prepared by the treatment of amide Ii (where X X ⁇ ⁇ O) with Lawesson's reagent as described above.
• Carbamate II can be prepared by treatment of amine compound Ii with a chloroformate 9 or dicarbonate 10 in the presence of an acid scavenger such as diisopropylethylamine.
• the corresponding thiourea In may be prepared by treatment of amine compound Ii with a thioisocyanate 13b.
• R 2 any group as defined other than acyl
• R 3 alkyl, cycloalkyl, cycloalkylalkyl, cycloalkenylalkyl, aralkyl or saturated heterocycle
• Scheme V illustrates a method which can be used for the preparation of Ip, which is a compound of the formula I where R 2 is any group as defined other than acyl, and which is selected such that the nitrogen to which it is attached is basic, R 3 is alkyl, cycloalkyl, cycloalkylalkyl, cycloalkenylalkyl, aralkyl, or saturated heterocycle, and X j _ and X JJ are not hydrogen.
• the starting compounds lo and Iq can be prepared by suitable methods described in Schemes A and D.
• amine compound lo is reacted with an aldehyde or ketone 14 under reductive amination conditions described above to give the amine Ip.
• Compound Ip may also be prepared by treatment of an amine compound Iq, where R 2 and R 3 are hydrogen, with t-butyl nitrite or sodium nitrite in the presence of a copper (II) halide to give the halo-substituted compound 15, followed by displacement with amine 16 in the presence of a base such as sodium or potassium hydride or the like (see Lee et al., J. Heterocyclic Chemistry, 22, 1621 (1985)).
• R d and R e are independently selected from hydrogen, alkyl, aryl, cycloalkyl or cycloalkenyl, or together are alkylene or alkenylene completing a 3- to 8-membered saturated or unsaturated ring, such that the group -CH(R d )(R e ) is a group within the definition of R 3 .
• R 2 any group as defined other than acyl
• R 3 aryl, heteroaryl
• amine compound Ir when R 2 is any group as defined other than acyl, and is selected such that the nitrogen to which it is attached is basic, R 3 is aryl or heteroaryl, and X and ⁇ are not hydrogen, amine compound Ir may be reacted with a halophenyl or haloheteroaromatic group 17 in the presence of a palladium (0) catalyst (see J. Am. Chem. Soc, 118, 7215 (1996)) to give amine Is, which is a compound of the formula I having the particular substituents described in this Scheme.
• the starting compound Ir can be prepared by suitable methods described in Schemes A and D.
• R 2 any group as defined
• R 3 heteroaryl
• amine compound it may be reacted, in the presence of a base if needed, with a 2-halosubstituted heteroaromatic compound 17 where Q 1? together with atoms to which is is bonded, forms a 5- or 6-membered monocyclic or 10- to 12-membered bicyclic heteroaromatic group (such as forming 2-chloropyridine or 2- chloropyrimidine) to give the amine lu, where lu is a compound of the formula I having the particular substituents described in this Scheme.
• the starting compound It can be prepared by suitable methods described in Schemes A and D.
• thiourea compound In (where X x and j are not hydrogen) may be reacted with the appropriate amine in the presence of bis-(2-oxo-3-oxazolidinyl)phosphinic chloride (BOP chloride) benzotriazol-l-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (BOP-reagent), [0-(7-azabenzotriazol-l-yl)-l, 1,3,3- tetramethyluronium]hexafluorophosphate (HATU) and carbodiimide, such as dicyclohexyl carbodiimide (DCC) or 3-ethyl-3'-(dimethylamino)propyl carbodiimide (EDCI) or diisopropyl carbodiimide (DIG) in the presence of an organic base such as triethylamine, diisopropylethylamine or di
• amine Ir (where X x and j are not hydrogen) can be reacted with diphenylcyanocarbonimidate either alone or in the presence of a base such as sodium hydride, sodium hexamethyldisilazide or dimethylaminopyridine in acetonitrile, tetrahydrofuran, or dimethylformamide at room temperature or elevated temperature to form intermediate compound Iw.
• a base such as sodium hydride, sodium hexamethyldisilazide or dimethylaminopyridine in acetonitrile, tetrahydrofuran, or dimethylformamide at room temperature or elevated temperature
• Compound Iw can be reacted with an amine R 7 R 8 NH to form compound Iv, which is a compound of the formula I having the particular substituents described in this Scheme.
• compound Ir (where X x and X ⁇ are not hydrogen) can be reacted with 18 or 19 either alone or in the presence of a base such as sodium hydride, sodium hexamethyl disilazide or dimethylaminopyridine in dimethyl formamide or tetrahydrofuran at room temperature or at higher temperature to form compounds Ix or Iy respectively, which can be reacted with an amine R 7 R 8 NH at room temperature or elevated temperature to form compounds Iz or Iz* respectively.
• a base such as sodium hydride, sodium hexamethyl disilazide or dimethylaminopyridine in dimethyl formamide or tetrahydrofuran at room temperature or at higher temperature to form compounds Ix or Iy respectively, which can be reacted with an amine R 7 R 8 NH at room temperature or elevated temperature to form compounds Iz or Iz* respectively.
• Compound Iz is a compound of the formula I having the particular substituents described in this Scheme.
• Compound Iz* is
• R 2 aryl, heteroaryl, bicyclic-heteroaryl
• R 3 H, alkyl, aryl, heteroaryl, bicyclic-heteroaryl
• compounds of formula I can also be prepared from 15 by treatment with the defined amine in the presence of an acid catalyst (for example, see: Gunzenhauser et al., Helv. Chim. Ada, 71, 33 (1988)).
• the present invention further provides compounds of formula III:
• each Ri, R 3 and R 4 is, independently, a heterocyclic group or an aryl group, optionally substituted with one or more substituents; and R 2 is hydrogen or alkyl.
• a preferred compound of the present invention is of formula IV:
• the compounds of the present invention inhibit protein tyrosine kinases, especially Src-family kinases such as Lck, Fyn, Lyn, Src, Yes, Hck, Fgr and Blk, and are thus useful in the treatment, including prevention and therapy, of protein tyrosine kinase-associated disorders such as immunologic and oncologic disorders.
• the compounds inhibit also receptor tyrosine kinases including HER1 and HER2 and are therefore useful in the treatment of proliferative disorders such as psoriasis and cancer.
• the ability of these compounds to inhibit HER1 and other receptor kinases will also permit their use as anti-angiogenic agents to treat disorders such as cancer and diabetic retinopathy.
• Protein tyrosine kinase-associated disorders are those disorders which result from aberrant tyrosine kinase activity, and/or which are alleviated by the inhibition of one or more of these enzymes.
• Lck inhibitors are of value in the treatment of a number of such disorders (for example, the treatment of autoimmune diseases), as Lck inhibition blocks T cell activation.
• the treatment of T cell mediated diseases, including inhibition of T cell activation and proliferation, is a particularly preferred embodiment of the present invention. Compounds which selectively block T cell activation and proliferation are preferred.
• the present invention thus provides methods for the treatment of protein tyrosine kinase-associated disorders, comprising the step of administering to a subject in need thereof at least one compound of the formula I in an amount effective therefor.
• Other therapeutic agents such as those described below may be employed with the inventive compounds in the present methods.
• such other therapeutic agent(s) may be administered prior to, simultaneously with or following the administration of the compound(s) of the present invention.
• transplant such as organ transplant, acute transplant or heterograft or homograft (such as is employed in burn treatment)
• protection from ischemic or reperfusion injury such as ischemic or reperfusion injury incurred during organ transplantation, myocardial infarction, stroke or other causes
• transplantation tolerance induction arthritis (such as rheumatoid arthritis, psoriatic arthritis or osteoarthritis); multiple sclerosis; chronic obstructive pulmonary disease (COPD), such as emphysema; inflammatory bowel disease, including ulcerative colitis and Crohn's disease; lupus (systemic lupus erythematosis); graft vs.
• transplant such as organ transplant, acute transplant or heterograft or homograft (such as is employed in burn treatment)
• protection from ischemic or reperfusion injury such as ischemic or reperfusion injury incurred during organ transplantation, myocardial infarction, stroke or other causes
• transplantation tolerance induction arthritis (such as rhe
• T-cell mediated hypersensitivity diseases including contact hypersensitivity, delayed-type hypersensitivity, and gluten-sensitive enteropathy (Celiac disease); psoriasis; contact dermatitis (including that due to poison ivy); Hashimoto's thyroiditis; Sjogren's syndrome; Autoimmune Hyperthyroidism, such as Graves' Disease; Addison's disease (autoimmune disease of the adrenal glands); Autoimmune polyglandular disease (also known as autoimmune polyglandular syndrome); autoimmune alopecia; pernicious anemia; vitiligo; autoimmune hypopituatarism; Guillain-Barre syndrome; other autoimmune diseases; cancers, including cancers where Lck or other Src-family kinases such as Src are activated or overexpressed, such as colon carcinoma and thymoma, and cancers where Src-family kinase activity facilitates tumor growth or survival; glomerulonephritis; serum sickness; uticaria
• Src-family kinases other than Lck are important in the Fc gamma receptor responses of monocytes and macrophages.
• Compounds of the present invention inhibit the Fc gamma dependent production of TNF alpha in the monocyte cell line THP-1 that does not express Lck.
• the ability to inhibit Fc gamma receptor dependent monocyte and macrophage responses results in additional anti- inflammatory activity for the present compounds beyond their effects on T cells. This activity is especially of value, for example, in the treatment of inflammatory diseases such as arthritis or inflammatory bowel disease.
• the present compounds are of value for the treatment of autoimmune glomerulonephritis and other instances of glomerulonephritis induced by deposition of immune complexes in the kidney that trigger Fc gamma receptor responses leading to kidney damage.
• Src family kinases other than Lck such as Lyn and Src, are important in the Fc epsilon receptor induced degranulation of mast cells and basophils that plays an important role in asthma, allergic rhinitis, and other allergic disease.
• Fc epsilon receptors are stimulated by IgE-antigen complexes.
• Compounds of the present invention inhibit the Fc epsilon induced degranulation responses, including in the basophil cell line RBL that does not express Lck.
• the ability to inhibit Fc epsilon receptor dependent mast cell and basophil responses results in additional anti-inflammatory activity for the present compounds beyond their effect on T cells.
• the present compounds are of value for the treatment of asthma, allergic rhinitis, and other instances of allergic disease.
• the combined activity of the present compounds towards monocytes, macrophages, T cells, etc. may be of value in the treatment of any of the aforementioned disorders.
• the compounds of the present invention are useful for the treatment of the aforementioned exemplary disorders irrespective of their etiology, for example, for the treatment of transplant rejection, rheumatoid arthritis, multiple sclerosis, chronic obstructive pulmonary disease, inflammatory bowel disease, lupus, graft v. host disease, T-cell mediated hypersensitivity disease, psoriasis, Hashimoto's thyroiditis, Guillain-Barre syndrome, cancer, contact dermatitis, allergic disease such as allergic rhinitis, asthma, ischemic or reperfusion injury, or atopic dermatitis whether or not associated with PTK.
• compounds of the present invention can also be used for the treatment of proliferative diseases, including psoriasis and cancer.
• the HER1 receptor kinase has been shown to be expressed and activated in many solid tumors including non-small cell lung, colorectal, and breast cancer.
• the HER2 receptor kinase has been shown to be overexpressed in breast, ovarian, lung and gastric cancer.
• Monoclonal antibodies that downregulate the abundance of the HER2 receptor or inhibit signaling by the HERl receptor have shown anti-tumor effficacy in preclincal and clinical studies.
• inhibitors of the HERl and HER2 kinases will have efficacy in the treatment of tumors that depend on signaling from either of the two receptors.
• These compounds are expected to have efficacy either as single agent or in combination with other chemotherapeutic agents such as placlitaxel (Taxol), doxorubicin hydrochloride (adriamycin), and cisplatin (Platinol).
• chemotherapeutic agents such as placlitaxel (Taxol), doxorubicin hydrochloride (adriamycin), and cisplatin (Platinol).
• the compounds of the present invention are useful for the treatment of cancers such as chronic myelogenous leukemia (CML), gastrointestinal stromal tumor (GIST), small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), ovarian cancer, melanoma, mastocytosis, germ cell tumors, acute myelogenous leukemia (AML), pediatric sarcomas, breast cancer, colorectal cancer, pancreatic cancer, prostate cancer and others known to be associated with protein tyrosine kinases such as, for example, SRC, BCR-ABL and c-KIT.
• the compounds of the present invention are also useful in the treatment of cancers that are sensitive to and resistant to chemotherapeutic agents that target BCR-ABL and c-KIT, such as, for example, Gleevec® (STI-571).
• the present invention also provides pharmaceutical compositions comprising at least one of the compounds of the formula I capable of treating a protein tyrosine kinase-associated disorder in an amount effective therefor, and a pharmaceutically acceptable vehicle or diluent.
• the compositions of the present invention may contain other therapeutic agents as described below, and may be formulated, for example, by employing conventional solid or liquid vehicles or diluents, as well as pharmaceutical additives of a type appropriate to the mode of desired administration (for example, excipients, binders, preservatives, stabilizers, flavors, etc.) according to techniques such as those well known in the art of pharmaceutical formulation.
• the compounds of the formula I may be administered by any suitable means, for example, orally, such as in the form of tablets, capsules, granules or powders; sublingually; buccally; parenterally, such as by subcutaneous, intravenous, intramuscular, or intrasternal injection or infusion techniques (e.g., as sterile injectable aqueous or non-aqueous solutions or suspensions); nasally such as by inhalation spray; topically, such as in the form of a cream or ointment; or rectally such as in the form of suppositories; in dosage unit formulations containing non-toxic, pharmaceutically acceptable vehicles or diluents.
• suitable means for example, orally, such as in the form of tablets, capsules, granules or powders; sublingually; buccally; parenterally, such as by subcutaneous, intravenous, intramuscular, or intrasternal injection or infusion techniques (e.g., as sterile injectable aqueous or non
• the present compounds may, for example, be administered in a form suitable for immediate release or extended release. Immediate release or extended release may be achieved by the use of suitable pharmaceutical compositions comprising the present compounds, or, particularly in the case of extended release, by the use of devices such as subcutaneous implants or osmotic pumps.
• the present compounds may also be administered liposomally.
• compositions for oral administration include suspensions which may contain, for example, microcrystalline cellulose for imparting bulk, alginic acid or sodium alginate as a suspending agent, methylcellulose as a viscosity enhancer, and sweeteners or flavoring agents such as those known in the art; and immediate release tablets which may contain, for example, microcrystalline cellulose, dicalcium phosphate, starch, magnesium stearate and or lactose and or other excipients, binders, extenders, disintegrants, diluents and lubricants such as those known in the art.
• the present compounds may also be delivered through the oral cavity by sublingual and/or buccal administration.
• Molded tablets, compressed tablets or freeze-dried tablets are exemplary forms which may be used.
• Exemplary compositions include those formulating the present compound(s) with fast dissolving diluents such as mannitol, lactose, sucrose and/or cyclodextrins. Also included in such formulations may be high molecular weight excipients such as celluloses (avicel) or polyethylene glycols (PEG).
• Such formulations may also include an excipient to aid mucosal adhesion such as hydroxy propyl cellulose (HPC), hydroxy propyl methyl cellulose (HPMC), sodium carboxy methyl cellulose (SCMC), maleic anhydride copolymer (e.g., Gantrez), and agents to control release such as polyacrylic copolymer (e.g., Carbopol 934).
• HPC hydroxy propyl cellulose
• HPMC hydroxy propyl methyl cellulose
• SCMC sodium carboxy methyl cellulose
• maleic anhydride copolymer e.g., Gantrez
• agents to control release such as polyacrylic copolymer (e.g., Carbopol 934).
• Lubricants, glidants, flavors, coloring agents and stabilizers may also be added for ease of fabrication and use.
• compositions for nasal aerosol or inhalation administration include solutions in saline which may contain, for example, benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailabihty, and/or other solubilizing or dispersing agents such as those known in the art.
• compositions for parenteral administration include injectable solutions or suspensions which may contain, for example, suitable non-toxic, parenterally acceptable diluents or solvents, such as mannitol, 1,3-butanediol, water, Ringer's solution, an isotonic sodium chloride solution, or other suitable dispersing or wetting and suspending agents, including synthetic mono- or diglycerides, and fatty acids, including oleic acid.
• suitable non-toxic, parenterally acceptable diluents or solvents such as mannitol, 1,3-butanediol, water, Ringer's solution, an isotonic sodium chloride solution, or other suitable dispersing or wetting and suspending agents, including synthetic mono- or diglycerides, and fatty acids, including oleic acid.
• compositions for rectal administration include suppositories which may contain, for example, a suitable non-irritating excipient, such as cocoa butter, synthetic glyceride esters or polyethylene glycols, which are solid at ordinary temperatures, but liquify and/or dissolve in the rectal cavity to release the drug.
• a suitable non-irritating excipient such as cocoa butter, synthetic glyceride esters or polyethylene glycols, which are solid at ordinary temperatures, but liquify and/or dissolve in the rectal cavity to release the drug.
• exemplary compositions for topical administration include a topical carrier such as Plastibase (mineral oil gelled with polyethylene).
• the effective amount of a compound of the present invention may be determined by one of ordinary skill in the art, and includes exemplary- dosage amounts for an adult human of from about 0.1 to 100 mg/kg of body weight of active compound per day, which may be administered in a single dose or in the form of individual divided doses, such as from 1 to 4 times per day. It will be understood that the specific dose level and frequency of dosage for any particular subject may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the species, age, body weight, general health, sex and diet of the subject, the mode and time of administration, rate of excretion, drug combination, and severity of the particular condition.
• Preferred subjects for treatment include animals, most preferably mammalian species such as humans, and domestic animals such as dogs, cats and the like, subject to protein tyrosine kinase-associated disorders.
• the compounds of the present invention are preferably administered using the formulations of the invention.
• the compounds of the present invention, including compounds of formula in and IV are administered by IV infusion over a period of from about 10 minutes to about 3 hours, preferably about 30 minutes to about 2 hours, more preferably about 45 minutes to 90 minutes, and most preferably about 1 hour.
• the compounds are administered intravenously in a dose of from about 0.5 mg/m 2 to 65 mg/m 2 , preferably about 1 mg/m 2 to 50 mg/m 2 , more preferably about 2.5 mg/m 2 to 30 mg/m 2 , and most preferably about 25 mg/m 2 .
• compounds of the present invention can be administered orally, intravenously, or both.
• the methods of the invention encompass dosing protocols such as once a day for 2 to 10 days, preferably every 3 to 9 days, more preferably every 4 to 8 days and most preferably every 5 days.
• the compounds of the present invention, including compounds of formulae HI or IV can be administered orally, intravenously, or both, once a day for 3 days, with a period of preferably 1 week to 3 weeks in between cycles where there is no treatment.
• the compounds of the present invention, including compounds of formulae HI or IV can be administered orally, intravenously, or both, once a day for 5 days, with a period of preferably 1 week to 3 weeks in between cycles where there is no treatment.
• the treatment cycle for administration of the compounds of the present invention is once daily for 5 consecutive days and the period between treatment cycles is from 2 to 10 days, preferably one week.
• a compound of the present invention for example, a compound of formula HI or formula IV, is administered once daily for 5 consecutive days, followed by 2 days when there is no treatment.
• the compounds of the present invention can also be administered orally, intravenously, or both once every 1 to 10 weeks, preferably every-2 to 8 weeks, more preferably every 3 to 6 weeks, and even more preferably every 3 weeks.
• the compounds of the present invention including compounds of formulae HI or IV, are administered in a 28 day cycle wherein the compounds are intravenously administered on days 1, 7, and 14 and orally administered on day 21.
• the compounds of the present invention, including compounds of formulae HI or IV are administered in a 28 day cycle wherein the compound of formulae I and H are orally administered on day 1 and intravenously administered on days 7, 14, and 28.
• the compounds of the present invention, including compounds of formulae III or IV are administered until the patient shows a response, for example, a reduction in tumor size, or until dose limiting toxicity is reached.
• the compounds of the present invention may be employed alone or in combination with each other and/or other suitable therapeutic agents useful in the treatment of protein tyrosine kinase-associated disorders such as PTK inhibitors other than those of the present invention, antiinflammatories, antiproliferatives, chemotherapeutic agents, immunosuppressants, anticancer agents and cytotoxic agents.
• suitable therapeutic agents useful in the treatment of protein tyrosine kinase-associated disorders such as PTK inhibitors other than those of the present invention, antiinflammatories, antiproliferatives, chemotherapeutic agents, immunosuppressants, anticancer agents and cytotoxic agents.
• cyclosporins e.g., cyclosporin A
• CTLA4-Ig antibodies such as anti- ICAM-3, anti-IL-2 receptor (Anti-Tac), anti-CD45RB, anti-CD2, anti-CD3 (OKT-3), anti-CD4, anti-CD80, anti-CD86, monoclonal antibody OKT3, agents blocking the interaction between CD40 and gp39, such as antibodies specific for CD40 and/or gp39 (i.e., CD154), fusion proteins constructed from CD40 and gp39 (CD40Ig and CD8gp39), inhibitors, such as nuclear translocation inhibitors, of NF-kappa B function, such as deoxyspergualin (DSG), non-steroidal antiinflammatory drugs (NSAIDs) such as ibuprofen, steroids such as prednisone or dexamethasone, gold compounds, antiproliferative agents such as methotrexate, FK506
• cyclosporins e.g.,
• 60/056,770 filed 8/25/97 (Attorney Docket No. QA202*), Serial No. 60/069,159, filed 12/9/97 (Attorney Docket No. QA202a*), Serial No. 09/097,338, filed 6/15/98 (Attorney Docket No. QA202b), Serial No. 60/056,797, filed 8/25/97 (Attorney Docket No. QA205*), Serial No. 09/094,797, filed 6/15/98 (Attorney Docket No. QA205a), Serial No. 60/065,042, filed 11/10/97 (Attorney Docket No. QA207*), Serial No.
• anti-cancer agents and cytotoxic agents include, but are not limited to: alkylating agents, such as nitrogen mustards, alkyl sulfonates, nitrosoureas, ethylenimines, and triazenes; antimetabolites, such as folate antagonists, purine analogues, and pyrimidine analogues; antibiotics, such as anthracyclines, bleomycins, mitomycin, dactinomycin, and plica ycin; enzymes, such as L-asparaginase; farnesyl-protein transferase inhibitors; hormonal agents, such as glucocorticoids, estrogens/antiestrogens, androgens/antiandrogens, progestins, and luteinizing hormone-releasing hormone anatagonists, octreotide acetate; microtubule-disruptor agents, such as ecteinascidins or then- analogs and derivatives;
• the compounds of the invention may also be used in conjunction with radiation therapy.
• Representative examples of these classes of anti-cancer and cytotoxic agents include, but are not limited to, mechlorethamine hydrochlordie, cyclophosphamide, chlorambucil, melphalan, ifosfamide, busulfan, carmustin, lomustine, semustine, streptozocin, thiotepa, dacarbazine, methotrexate, thioguanine, mercaptopurine, fludarabine, pentastatin, cladribin, cytarabine, fluorouracil, doxorubicin hydrochloride, daunorubicin, idarubicin, bleomycin sulfate, mitomycin C, actinomycin D, safracins, saframycins, quinocarcins, discodermolides, vincristine, vmblastine, vinorel
• Preferred members of these classes include, but are not limited to paclitaxel, cisplatin, carboplatin, doxorubicin, carminomycin, daunorubicin, aminopterin, methotrexate, methopterin, mitomycin C, ecteinascidin 743, porfirornycin, 5-fluorouracil, 6-mercaptopurine, gemcitabine, cytosine arabinoside, podophyllotoxin or podophyllotoxin derivatives such as etoposide, etoposide phosphate or teniposide, melphalan, vinblastine, vincristine, leurosidine, vindesine, and leurosine.
• anti-cancer and other cytotoxic agents include the following: epothHone derivatives as found in U.S. Serial No. 09/506,481 filed February 17, 2000 (Attorney Docket No. LD186); German Patent No. 4138042.8; WO 97/19086, WO 98/22461, WO 98/25929, WO 98/38192, WO 99/01124, WO 99/02224, WO 99/02514, WO 99/03848, WO 99/07692, WO 99/27890, WO 99/28324, WO 99/43653, WO 99/54330, WO 99/54318, WO 99/54319, WO 99/65913, WO 99/67252, WO 99/67253, and WO 00/00485; cyclin dependent kinase inhibitors as found in WO 99/24416; and prenyl-protein transferase inhibitors as found in WO 97/30992 and WO
• test compound a compound as a PTK inhibitor.
• test compound a compound described in the following Examples have been tested in one or more of these assays, and have shown activity.
• Enzyme Assay Using Lck, Fyn, Lyn, Hck, Fgr, Src, Blk or Yes The following assay has been carried out using the protein tyrosine kinases Lck, Fyn, Lyn, Hck, Fgr, Src, Blk and Yes.
• the protein tyrosine kinase of interest is incubated in kinase buffer (20 mM MOPS, ⁇ H7, 10 mM MgCl 2 ) in the presence of the test compound.
• the reaction is initiated by the addition of substrates to the final concentration of 1 ⁇ M ATP, 3.3 ⁇ Ci/ml [33P] gamma-ATP, and 0.1 mg/ml acid denatured enolase (prepared as described in Cooper, J.A., Esch, F.S., Taylor, S.S., and Hunter, T., "Phosphorylation sites in enolase and lactate dehydrogenase utilized by tyrosine protein kinases in vivo and in vitro", J.
• This assay is advantageous as it employs an exogenous substrate (enolase) for more accurate enzyme kinetics, and can be conducted in a 96- well format that is readily automated.
• Enolase exogenous substrate
• His-tagged protein tyrosine kinases (described below) offer much higher production yields and purity relative to GST-protein tyrosine kinase fusion protein.
• the protein tyrosine kinase may be obtained from commercial sources or by recombinant methods described herewith.
• human Lck was prepared as a His-tagged fusion protein using the Life Technologies (Gibco) baculovirus vector pFastBac Hta (commercially available) in insect cells.
• pFastBac Hta commercially available
• a cDNA encoding human Lck isolated by PCR (polymerase chain reaction) was inserted into the vector and the protein was expressed using the methods described by the manufacturer.
• the Lck was purified by affinity chromatography.
• kinase buffer that contained 20 mM Tris.HCl, pH 7.5, 10 mM MnCl 2 , 0.5 mM dithiothreitol, bovine serum albumin at 0.1 mg/ml, poly(glu/tyr, 4:1) at 0.1 mg/ml, l ⁇ M ATP, and 4 ⁇ Ci/ml [gamma- 33 P]ATP.
• Poly(glu/tyr, 4:1) is a synthetic polymer that serves as a phosphoryl acceptor and is purchased from Sigma Chemicals. The kinase reaction is initiated by the addition of enzyme and the reaction mixtures were incubated at 26°C for 1 h.
• HERl cytoplasmic sequence of the receptor were expressed in insect cells as a GST fusion protein, which was purified by affinity chromatography as described above for Lck.
• the cytoplasmic sequence of HER2 was subcloned into the baculovirus expression vector pBlueBac4 (Invitrogen) and was expressed as an untagged protein in insect cells.
• the recombinant protein was partially purified by ion-exchange chromatography.
• Jurkat T cells are incubated with the test compound and then stimulated by the addition of antibody to CD3 (monoclonal antibody G19- 4). Cells are lysed after 4 minutes or at another desired time by the addition of a lysis buffer containing NP-40 detergent. Phosphorylation of proteins is detected by anti-phosphotyrosine immunoblotting. Detection of phosphorylation of specific proteins of interest such as ZAP-70 is detected by immunoprecipitation with anti-ZAP-70 antibody followed by anti- phosphotyrosine immunoblotting.
• Calcium assay Lck inhibitors block calcium mobilization in T cells stimulated with anti-CD3 antibodies.
• Cells are loaded with the calcium indicator dye indo- 1, treated with anti-CD3 antibody such as the monoclonal antibody G19-4, and calcium mobilization is measured using flow cytometry by recording changes in the blue/violet indo-1 ratio as described in Schieven, G.L., Mittler, R.S., Nadler, S.G., Kirihara, J.M., Bolen, J.B., Kanner, S.B., and Ledbetter, J.A., "ZAP-70 tyrosine kinase, CD45 and T cell receptor involvement in UV and H 2 0 2 induced T cell signal transduction", J. Biol. Chem., 269, 20718-20726 (1994), and the references incorporated therein.
• Lck inhibitors inhibit the proliferation of normal human peripheral blood T cells stimulated to grow with anti-CD3 plus anti-CD28 antibodies.
• a 96 well plate is coated with a monoclonal antibody to CD3 (such as G19- 4), the antibody is allowed to bind, and then the plate is washed. The antibody bound to the plate serves to stimulate the cells.
• Normal human peripheral blood T cells are added to the wells along with test compound plus anti-CD28 antibody to provide co-stimulation. After a desired period of time (e.g., 3 days), the [3H]-thymidine is added to the cells, and after further incubation to allow incorporation of the label into newly synthesized DNA, the cells are harvested and counted in a scintillation counter to measure cell proliferation.
• TFA trifluoroacetic acid
• THF tetrahydrofuran
• Ethyl-2-feri ⁇ butoxycarbonyloxyamino-4-methyl-thiazole-5-earboxylate A suspension of ethyl-2-amino-4-methyl-thiazole-5-carboxylate (18.6 g, 100 mmol), di-t-butyldicarbonate (26.2 g, 120 mmol) and 4- dimethylaminopyridine (800 mg, 6.55 mmol) in dry tetrahydrofuran (300 mL) was stirred under nitrogen for 18 h. The solvent was evaporated in vacuo. The residue was suspended in dichloromethane (1 L) and filtered through a pad of celite.
• Compound 5C was prepared by an analogous method as that of IC, except using 5B to give the title compound 5C as a white solid (90%).
• Compound 5D was prepared by an analogous method as that of ID, except using 5C to give the title compound 5D as a light yellow solid (93%).
• Compound 11A was prepared by an analogous method as that of 3A, except using ethyl-2-amino-thiazole-5-carboxylate to give the title compound 11A as a white solid (79.5%).
• Compound 11B was prepared by an analogous method as that of 3B, except using HA to give the title compound 11B as a white solid (95.5%).
• Compound 11D was prepared by an analogous method as that of ID, except using 11C to give the title compound 11D as an off-white solid (70%).
• Compound 12 was prepared by an analogous method as that of 4, except using 11D to give the title compound 12 as a light yellow solid (88%).
• the column was washed sequentially with dichloromethane (9 mL), dichloromethane-methanol (9 mL, 4:1), dichloromethane-methanol (9 mL, 1:1), methanol (9 mL), 0.01 M ammonium hydroxide in methanol (9 mL) and 0.05 M ammonium hydroxide in methanol (9 mL).
• the elutes were collected separetely by the robot and then concentrated using a speed vac. Fractions containing the products were combined.
• ⁇ PLC Ret Time is the HPLC retention time under the following conditions: YMC S5 ODS 4.6 x 50 mm Ballastic Column, 4 min gradient starting from 100% solvent A (10% MeOH, 90% H 2 0, 0.2% H 3 P0 4 ) to 100% 04 0
• Compound 132 was prepared by an analogous method as that of 1, except using ethyl-2-fer ⁇ -butoxycarbonyloxyaminomethyl-4-methyl-thiazole-5- carboxylate to give the title compound 132 as a tan solid.
• Compound 133 was prepared by an analogous method as that of 4, except using 132 to give the title compound 133 as a white solid (91%).
• Compound 134 was prepared by an analogous method as that of 1, except using N-methyl-2,4,6-trimethylaniline to give the title compound 134 as a white solid (60%).
• Compound 138 was prepared by an analogous method as that of 4, except using 137 to give the title compound 138 as a white solid (89%).
• Compound 140 was prepared by an analogous method as that of 4, except using 53 to give the title compound 140 as a light tan solid (100%).
• Compound 141 was prepared by an analogous method as that of 4, except using 13 to give the title compound 141 as an off-white solid (100%).
• Compound 143 was prepared by an analogous method as that of 4, except using 15 to give the title compound 143 as a light tan solid (70%).
• Compound 144 was prepared by an analogous method as that of 4, except using 19 to give the title compound 144 as a light tan solid (81%).
• Compound 145 was prepared by an analogous method as that of 4, except using 17 to give the title compound 145 as a light tan solid (68%).
• Compound 146 was prepared by an analogous method as that of 4, except using 16 to give the title compound 146 as a light tan solid (100%).
• Compound 150 was prepared by an analogous method as that of 149, except using butyric anhydride to give the title compound 150 as a white solid (76%).
• Compound 151 was prepared by an analogous method as that of 149, except using valeric anhydride to give the title compound 151 as a white solid (77%).
• Compound 152 was prepared by an analogous method as that of 149, except using hexanoic anhydride to give the title compound 152 as a white solid (75%).
• Examples 156 to 170 General Procedure Compounds 156 to 170 were prepared following the procedure described below. Diisopropylethyl amine (60 ⁇ L, 0.34 mmol) was added to a mixture of amine 2 (30 mg, 0.11 mmol), appropriate carboxylic acid (0.13 mmol), 1- hydroxy-7-azabenzotriazole (19.5 mg, 0.14 mmol), and ethyl-3-(3- dimethylamino)-propyl carbodiimide hydrochloride (26.8 mg, 0.14 mmol) in THF (1 mL). The mixture was heated in a sealed tube under argon at 45 °C for 24 h.
• the reaction mixture was diluted with dichloromethane (4 L) and washed with 2 N aq. HCl solution (2 mL, 3x), dried (Na 2 S0 4 ) and concentrated using a speedvac.
• the crude products were either triturated with dichloromethane-ether (5 mL, 1:1) or purified by silica gel chromatography (elution solvent: 50% EtOAC in hexanes and EtOAc).
• the crude product was purified either by trituration with ether or ether-hexanes mixture, or by chromatography on a silica gel column (elution solvent 20-40% EtOAc in hexanes) followed by trituration or by passing through Varian cation exchange SCX cartridge and sequentially eluted with methanol (5 mL), dichloromethane (5 mL), acetonitrile-methanol (10 mL, 4:1) and methanol- 2 M methanolic ammonia (10 mL, 4:1) to obtain the title compound.
• Compound 307 was prepared following the procedure described below. A suspension solution of 2-[[(Butylamino)carbonyl]amino]-4-methyl-5- thiazole carboxylic acid (100 mg, 0.36 mmol), and HATU (170 mg, 0.44 mmol) in DMF (3 mL) was treated with diisopropylethyl amine (62 mL, 0.44 mmol). The mixture was heated to 60°C for 2 h, cooled, diluted with dichloromethane (12 mL), washed with 8M aq. Urea solution in 2 N aq. HCl (6 mL, 3x), 5% aq.
• ⁇ PLC Ret Time is the HPLC retention time under the following conditions: YMC S5 ODS 4.6 x 50 mm Ballastic Column, 4 min gradient starting from 100% solvent A (10% MeOH, 90% H 2 0, 0.2% H 3 P0 4 ) to 100% 04/085388
• Diisopropylethylamine (87 ⁇ L, 0.5 mmol) was added to a solution of 312 B (99 mg, 0.42 mmol), 2,4,6-trimethylaniline (68 ⁇ L, 0.5 mmol), and [0-(7- azabenzotriazol-l-yl)-l,l,3,3-tetramethyluronium]hexafluorophosphate (HATU, 191 mg, 0.5 mmol) in DMF (3 mL). The mixture was stirred at rt overnight, diluted with EtOAc and washed with 0.5 N aq. HCl solution (15 mL), 10% aq.
• Compound 314 was prepared by an analogous method as that of compounds 171-180, using ethylisocyanate to give the title compound 314 as a white solid (65%).
• Compound 317 was prepared by an analogous method as that of 1, except using methyl-2-amino-4-methyl-thiazole-5-acetate to give the title compound 317 as an off-white solid.
• Compound 318 was prepared by an analogous method as that of 2, except using 317 to give the title compound 318 as a light brown solid.
• Compound 320 was prepared by an analogous method as that of 319B, except using 4-ethyl-2-amino ⁇ yridine to give the title compound 320.
• Compound 321 was prepared by an analogous method as that of 319B, except using 2,6-dimethyl-4-aminopyrimidine to give the title compound 321.
• Compound 322 was prepared by an analogous method as that of 319B, except using 3-aminopyridazine to give the title compound 322.
• the reaction mixture was diluted with dichloromethane (4 mL) and washed with 1 N aq. HCl solution.
• the dichloromethane solution was passed through a Varian Mega Bond Elut SCX cation exchange column (prewashed with methanol and equilibrated with acetonitrile- methanol (4:1).
• the column was eluted sequentially with acetonitrile- methanol (4:1), methanol-2M methanolic ammonia (4:1). Fractions containing the product were combined and concentrated in vacuo.
• HPLC Ret Time is the HPLC retention time under the following conditions: YMC S5 ODS 4.6 x 50 mm Ballastic Column, 4 min gradient starting from 100% solvent A (10% MeOH, 90% H20, 0.2% H3P04 ) to 0
• ⁇ PLC Ret Time is the HPLC retention time under the following conditions: YMC S5 ODS 4.6 x 50 mm Ballastic Column, 4 min gradient starting from 100% solvent A (10% MeOH, 90% H20, 0.2% H3P04 ) to 04/085388
• Compound 363 was prepared by an analogous method as that of 315, except using 2,6-dimethylaniline to give the title compound 363.
• Compound 364 was prepared by an analogous method as that of 315, except using 2,4, 6-trimethylaniline to give the title compound 364.
• Compound 365 was prepared by an analogous method as that of 315, except using 2-chloro-4,6-dimethylaniline to give the title compound 365. 004/085388
• Compound 366 was prepared by an analogous method as that of 1 except, using 2-tert-butoxycarbonyloxyamino-thiazole-4-acetic acid to give the title compound 366 as a white solid.
• Compound 371 was prepared by an analogous method as that of 1, except using 2-tert-butoxycarbonyloxyamino-4-methyl-5-oxazolecarboxylic acid to give the title compound 371 as a light yellow foam.
• Compound 372 was prepared by an analogous method as that of 4, except using 369 to give the title compound 372 as a white solid.
• Compound 373 was prepared by an analogous method as that of 3, except using 6-aminonicotinic acid to give the title compound 373 as a white solid.
• Compound 374 was prepared by an analogous method as that of 3, except using 3-amino-4-pyridinecarboxylic acid to give the title compound 374 as a white solid.
• Compound 375 was prepared by an analogous method as that of 3, except using 2-amino-4-methyl-5-pyrimidinecarboxylic acid to give the title compound 375 as a white solid. 04/085388
• Compound 376 was prepared by an analogous method as that of 319B, except using 2-amino-4-methyl-pyridine to give the title compound 376 as an off-white solid.
• Compound 378 was prepared by an analogous method as that of 319B, except using 2-amino-6-propyl-pyridine to give the title compound 378 as an off-white solid.
• Compound 379 was prepared by an analogous method as that of 319B, except using 4-amino-6-ethyl-pyrimidine to give the title compound 379 as a white solid.
• 1, 1-dimethylethyl ester Compound 410A was prepared by an analogous method as that of 315C, except using 2,6-dimethylaniline.
• Compound 428A was prepared by an analogous method as that of 315C, except using 2,4,6-trimethylaniline.
• Compound 428B was prepared by an analogous method as that of 315D, except using compound 428A.
• the title compound was prepared by an analogous method as that of 319B, except using compound 428B and 2-aminopyridine. HPLC Ret. Time 3.66min.
• Compound 462A was prepared by an analogous method as that of 444A, except using 4,6-dichloropyrimidine.
• Compound 481A was prepared by an analogous method as that of 473B, except using compound 2-chloro-6-aminopyrazine in place of compound 2- bromo-6-aminopyridine.
• Compound 406 was prepared by an analogous method as that of 473C, except using compound 481 A in place of compound 473B.
• Compound 487A was prepared by an analogous method as that of 473B, except using compound 3-chloro-5-aminopyridazine in place of compound 2-bromo-6-aminopyridine.
• Compound 487B was prepared by an analogous method as that of 473C, except using compound 487A in place of compound 473B.
• the title compound was prepared by an analogous method as that of 444B, except using compound 487B in place of compound 444A, and 3- hydroxypyrrolidine in place of N-(2-aminoethyl)-morpholine. HPLC Ret. Time 2.493min.
• Compound 488 was prepared by an analogous method as that of 487C, except using imidazole in place of 3-hydroxypyrrolidine. HPLC Ret. Time 2.61min. Example 489
• Compound 489A was prepared by an analogous method as that of 473B, except using compound 2-chloro-3-aminopyrazine in place of compound 2- bromo-6-aminopyridine.
• Compound 495 was prepared by an analogous method as that of 444B, except using compound 319A in place of compound 444A, and using cyclohexylamine in place of N-(2-aminoethyl)-morpholine. HPLC Ret. Time 3.547min.
• Compound 514A was prepared from 473A by an analogous method as that of 473B, except using 2-aminonapthaline in place of 2-bromo-6- aminopyridine.
• Compound 515A was prepared from 473A by an analogous method as that of 473B, except using 2-aminoquinoline in place of 2-bromo-6- aminopyridine .
• Compound 516A was prepared from 473A by an analogous method as that of 473B, except using 3-aminoisoquinoline in place of 2-bromo-6- aminopyridine .
• the title compound was prepared by an analogous method as that of 473C, except using compound 516A in place of compound 473B. HPLC Ret. Time 3.94min.
• Compound 517A was prepared from 473A by an analogous method as that of 473B, except using 2-aminoquinoxaline in place of 2-bromo-6- aminopyridine.
• the title compound was prepared by an analogous method as that of 473C, except using compound 517A in place of compound 473B. HPLC Ret. Time 3.927min.
• Compound 518A was prepared from 144 by an analogous method as that of 319A.
• Compound 518B was prepared by an analogous method as that of 473A, except using 518A in place of 319A.
• Compound 518C was prepared by an analogous method as that of 473B, except using 518B in place of 473A, and 4-amino-6-chloro-2- methylpyrimidine in place of 2-amino-6-bromopyridine.
• Compound 518D was prepared by an analogous method as that of 473C, except using 518C in place of 473B.
• Compound 519 was prepared by an analogous method as that of 518E, except using N-(2-aminoethyl)-morpholine in place of morpholine. HPLC Ret. Time 2.493min.
• Compound 520A was prepared from 2-aminothiazole according to the procedure described in UK Patent Application GB 2323595A.
• Compound 520C was prepared by a method analogous to that used for the preparation of compound 473A, using 520B in place of 319A.
• Compound 520D was prepared from compound 520C by a method analogous to that used for the preparation of compound 473B.
• Compound 521A was prepared by an analogous method as that of 520B, except using phenylisocyanate in place of 2-chloro-6- methylphenylisocyanate.
• Compound 521B was prepared by a method analogous to that used for the preparation of compound 473A, using 521A in place of 319A.
• Compound 521C was prepared from compound 521B by a method analogous to that used for the preparation of compound 473B.
• Compound 522A was prepared by an analogous method as that of 520B, except using 2-methylphenylisocyanate in place of 2-chloro-6- methylphenylisocyanate.
• Compound 522B was prepared by a method analogous to that used for the preparation of compound 473A, using 522A in place of 319A.
• Compound 522C was prepared from compound 522B by a method analogous to that used for the preparation of compound 473B.
• Compound 524A was prepared by an analogous method as that of 520B, except using 3,5-dimethoxyphenylisocyanate in place of 2-chloro-6- methylphenylisocyanate.
• Compound 524B was prepared by a method analogous to that used for the preparation of compound 473A, using 524A in place of 319A.
• Compound 524C was prepared from compound 524B by a method analogous to that used for the preparation of compound 473B.
• Compound 525A was prepared by an analogous method as that of 520B, except using 2,2-diisopropylphenylisocyanate in place of 2-chloro-6- methylphenylisocyanate.
• Compound 525B was prepared by a method analogous to that used for the preparation of compound 473A, using 525A in place of 319A.
• Compound 525C was prepared from compound 525B by a method analogous to that used for the preparation of compound 473B.
• Compound 529 was prepared in an analogous manner to 319B, except using 528 and 6-bromo-2-aminopyridine as the reactants.
• Compound 539 was prepared in an analogous manner to 319B, except using ethyl 2-bromo-5-thiazolecarboxylate and 6-bromo-2-aminopyridine as the reactants.
• Compound 551 was prepared in an analogous manner to 319B, except using ethyl 2-bromo-4-methyl-5-thiazolecarboxylate and 6-bromo-2- aminopyridine as the reactants.
• thiazolecarboxamide 319A an aniline (1 eq), 1.0 N aqueous HCl (0.5 eq)

Landscapes

• Health & Medical Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• General Health & Medical Sciences (AREA)
• Medicinal Chemistry (AREA)
• Pharmacology & Pharmacy (AREA)
• Life Sciences & Earth Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Chemical Kinetics & Catalysis (AREA)
• General Chemical & Material Sciences (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Engineering & Computer Science (AREA)
• Immunology (AREA)
• Dermatology (AREA)
• Epidemiology (AREA)
• Pulmonology (AREA)
• Diabetes (AREA)
• Hematology (AREA)
• Physical Education & Sports Medicine (AREA)
• Orthopedic Medicine & Surgery (AREA)
• Neurology (AREA)
• Urology & Nephrology (AREA)
• Rheumatology (AREA)
• Pain & Pain Management (AREA)
• Ophthalmology & Optometry (AREA)
• Oncology (AREA)
• Transplantation (AREA)
• Heart & Thoracic Surgery (AREA)
• Cardiology (AREA)
• Vascular Medicine (AREA)
• Biomedical Technology (AREA)
• Neurosurgery (AREA)
• Endocrinology (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Plural Heterocyclic Compounds (AREA)
• Nitrogen Condensed Heterocyclic Rings (AREA)
• Thiazole And Isothizaole Compounds (AREA)

Priority Applications (21)

Applications Claiming Priority (2)

Publications (2)

Family

ID=33096777

Family Applications (1)

Country Status (35)

Cited By (53)

Families Citing this family (63)

Citations (25)

Family Cites Families (79)

• 2003
  • 2003-03-24 US US10/395,503 patent/US7125875B2/en not_active Expired - Lifetime
• 2004
  • 2004-03-10 MY MYPI20040834A patent/MY139730A/en unknown
  • 2004-03-18 TW TW093107346A patent/TWI351404B/zh not_active IP Right Cessation
  • 2004-03-23 BR BRPI0408782-8A patent/BRPI0408782A/pt not_active Application Discontinuation
  • 2004-03-23 ES ES04758053T patent/ES2342937T5/es not_active Expired - Lifetime
  • 2004-03-23 SI SI200431447T patent/SI1610780T2/sl unknown
  • 2004-03-23 CA CA2519898A patent/CA2519898C/en not_active Expired - Lifetime
  • 2004-03-23 CN CNA2004800078458A patent/CN1764454A/zh active Pending
  • 2004-03-23 WO PCT/US2004/008827 patent/WO2004085388A2/en active Application Filing
  • 2004-03-23 NZ NZ542171A patent/NZ542171A/en unknown
  • 2004-03-23 UA UAA200509996A patent/UA87456C2/uk unknown
  • 2004-03-23 JP JP2006507475A patent/JP2006523216A/ja active Pending
  • 2004-03-23 RU RU2005132408/04A patent/RU2365372C2/ru active
  • 2004-03-23 DK DK04758053.5T patent/DK1610780T4/da active
  • 2004-03-23 RS YU20050698A patent/RS52291B/sr unknown
  • 2004-03-23 PL PL04758053.5T patent/PL1610780T5/pl unknown
  • 2004-03-23 CN CNA2006101724415A patent/CN1989969A/zh active Pending
  • 2004-03-23 CL CL200400610A patent/CL2004000610A1/es unknown
  • 2004-03-23 MX MXPA05010145A patent/MXPA05010145A/es active IP Right Grant
  • 2004-03-23 AT AT04758053T patent/ATE464898T1/de active
  • 2004-03-23 DE DE602004026703T patent/DE602004026703D1/de not_active Expired - Lifetime
  • 2004-03-23 EP EP04758053.5A patent/EP1610780B2/en not_active Expired - Lifetime
  • 2004-03-23 AU AU2004223828A patent/AU2004223828B2/en not_active Expired
  • 2004-03-23 FI FIEP04758053.5T patent/FI1610780T4/fi active
  • 2004-03-23 PT PT04758053T patent/PT1610780E/pt unknown
  • 2004-03-23 GE GEAP20048990A patent/GEP20074234B/en unknown
  • 2004-03-24 AR ARP040100964A patent/AR044506A1/es not_active Application Discontinuation
  • 2004-03-24 PE PE2004000312A patent/PE20041068A1/es not_active Application Discontinuation
• 2005
  • 2005-09-14 IL IL170873A patent/IL170873A/en active IP Right Grant
  • 2005-09-20 NO NO20054359A patent/NO336065B1/no unknown
  • 2005-09-20 HR HRP20050826AA patent/HRP20050826B8/hr not_active IP Right Cessation
  • 2005-09-21 IS IS8038A patent/IS8038A/is unknown
  • 2005-09-23 KR KR1020057017907A patent/KR101070101B1/ko active IP Right Review Request
  • 2005-09-23 ZA ZA200507718A patent/ZA200507718B/en unknown
• 2006
  • 2006-01-24 HK HK06101056.3A patent/HK1078491A1/xx not_active IP Right Cessation
• 2010
  • 2010-07-20 CY CY20101100674T patent/CY1110225T1/el unknown

Patent Citations (26)

Non-Patent Citations (29)

Also Published As

Similar Documents

Legal Events